The ADMA/DDAH Pathway Regulates VEGF-Mediated Angiogenesis

Objectives— Asymmetrical dimethylarginine (ADMA) is a nitric oxide synthase (NOS) inhibitor and cardiovascular risk factor associated with angiogenic disorders. Enzymes metabolising ADMA, dimethylarginine dimethylaminohydrolases (DDAH) promote angiogenesis, but the mechanisms are not clear. We hypothesized that ADMA/DDAH modifies endothelial responses to vascular endothelial growth factor (VEGF) by affecting activity of Rho GTPases, regulators of actin polymerization, and focal adhesion dynamics. Methods and Results— The effects of ADMA on VEGF-induced endothelial cell motility, focal adhesion turnover, and angiogenesis were studied in human umbilical vein endothelial cells (HUVECs) and DDAH I heterozygous knockout mice. ADMA inhibited VEGF-induced chemotaxis in vitro and angiogenesis in vitro and in vivo in an NO-dependent way. ADMA effects were prevented by overexpression of DDAH but were not associated with decreased proliferation, increased apoptosis, or changes in VEGFR-2 activity or expression. ADMA inhibited endothelial cell polarization, protrusion formation, and decreased focal adhesion dynamics, resulting from Rac1 inhibition after decrease in phosphorylation of vasodilator stimulated phosphoprotein (VASP). Constitutively active Rac1, and to a lesser extent dominant negative RhoA, abrogated ADMA effects in vitro and in vivo. Conclusion— The ADMA/DDAH pathway regulates VEGF-induced angiogenesis in an NO- and Rac1-dependent manner

Pancreatite em adulto com leucemia linfoblástica aguda usando L-asparaginase e sinvastatina: relato de caso e revisão sistemática

Context: Acute pancreatitis is a inflammatory process of the pancreas. It can be caused by gallstones, metabolic disorders, associated or not with alcohol abuse, or medication. Case Report: A 38-year-old man was admitted to the hospital because of worsening of nausea, abdominal pain, dizziness and white stool. Patient was diagnosed with severe acute pancreatitis. After six days of hospitalization, patient progressed into hypotension and severe bradycardia, and died. The patient used simvastatin chronically, and was in treat with L-asparaginase, both drugs related to the occurence of acute pancreatitis separately. Naranjo´s probability scale of adverse drug reaction established the causality between these medications and acute pancreatitis as probable. However, due to the absence of reports of causality, the acute pancreatitis is associated with to the use of L-asparaginase with possible drug interactions with simvastatin. Conclusion: It is very important to monitor patients treated with L-asparaginase, through careful observation of clinical signs and laboratory follow-up, as well as verification of other medications in use. The AP may have different levels of severity, being indispensable the quick diagnosis and early treatmentContexto: Pancreatite aguda é um processo inflamatório do pâncreas. É causada por cálculos biliares, desordens metabólicas, associadas ou não ao uso abusivo de álcool, ou medicamentos. Relato do Caso: Homem de 38 anos foi admitido no hospital em razão do agravamento de náuseas, dor abdominal, tontura e fezes brancas. O paciente foi diagnosticado com pancreatite aguda. Após seis dias de internação, paciente progrediu com hipotensão e bradicardia severa, evoluindo à óbito. O paciente fazia uso crônico de sinvastatina, e estava em tratamento com L-asparaginase, ambos fármacos, de modo separado, são relacionados com a ocorrência de pancreatite aguda severa. O algoritmo de Naranjo para estabelecimento de reação adversa a medicação classificou a causalidade entre as medicações citadas e a pancreatite aguda como provável. Porém, em razão da ausência relatos dessa causalidade, associa-se a pancreatite aguda ao uso de L-asparaginase, com possível interação medicamentosa com sinvastatina. Conclusão: É de suma importância o acompanhamento clínico e laboratorial de pacientes em uso de Lasparaginase para sinais de pancreatite aguda, sendo imprescindível o rápido diagnóstico e tratamento precoc

Climate simulation of the latest Permian: Implications for mass extinction

This report presents the results of climate modeling research which indicates that elevated levels of carbon dioxide in the atmosphere at the end of the Permian period led to climatic conditions inhospitable to both marine and terrestrial life. The Permian-Triassic boundary (about 251 million years ago) was the time of the largest known mass extinction in Earth's history, when greater than ninety percent of all marine species, and approximately seventy percent of all terrestrial species, died out. The model, which used paleogeography and paleotopography correct for the time period, indicated that warm high-latitude surface air temperatures and elevated carbon dioxide levels may have resulted in slowed circulation and stagnant, anoxic conditions in Earth's oceans. The report also suggests that the excess carbon dioxide (and sulfur dioxide) may have originated from volcanic activity associated with eruption of the Siberian Trap flood basalts, which took place at the same time. Educational levels: Undergraduate lower division, Undergraduate upper division, Graduate or professional

Explicit Evidence Systems with Common Knowledge

Justification logics are epistemic logics that explicitly include justifications for the agents' knowledge. We develop a multi-agent justification logic with evidence terms for individual agents as well as for common knowledge. We define a Kripke-style semantics that is similar to Fitting's semantics for the Logic of Proofs LP. We show the soundness, completeness, and finite model property of our multi-agent justification logic with respect to this Kripke-style semantics. We demonstrate that our logic is a conservative extension of Yavorskaya's minimal bimodal explicit evidence logic, which is a two-agent version of LP. We discuss the relationship of our logic to the multi-agent modal logic S4 with common knowledge. Finally, we give a brief analysis of the coordinated attack problem in the newly developed language of our logic

Single-vortex-induced voltage steps in Josephson-junction arrays

We have numerically and analytically studied ac+dc driven Josephson-junction arrays with a single vortex or with a single vortex-antivortex pair present. We find single-vortex steps in the voltage versus current characteristics (I-V) of the array. They correspond microscopically to a single vortex phase-locked to move a fixed number of plaquettes per period of the ac driving current. In underdamped arrays we find vortex motion period doubling on the steps. We observe subharmonic steps in both underdamped and overdamped arrays. We successfully compare these results with a phenomenological model of vortex motion with a nonlinear viscosity. The I-V of an array with a vortex-antivortex pair displays fractional voltage steps. A possible connection of these results to present day experiments is also discussed.Comment: 10 pages double sided with figures included in the text. To appear in Journal of Physics, Condensed Matte

Voltage rectification by a SQUID ratchet

We argue that the phase across an asymmetric dc SQUID threaded by a magnetic flux can experience an effective ratchet (periodic and asymmetric) potential. Under an external ac current, a rocking ratchet mechanism operates whereby one sign of the time derivative of the phase is favored. We show that there exists a range of parameters in which a fixed sign (and, in a narrower range, even a fixed value) of the average voltage across the ring occurs, regardless of the sign of the external current dc component.Comment: 4 pages, 4 EPS figures, uses psfig.sty. Revised version, to appear in Physical Review Letters (26 August 1996

Does mass drug administration for the integrated treatment of neglected tropical diseases really work? Assessing evidence for the control of schistosomiasis and soil-transmitted helminths in Uganda

This paper was one of four papers commissioned to review the role of social sciences in NTD control by TDR, the Special Programme for Research and Training on Tropical Diseases, which is executed by WHO and co-sponsored by UNICEF, UNDP, the World Bank and WHO.This article has been made available through the Brunel Open Access Publishing Fund.Background: Less is known about mass drug administration [MDA] for neglected tropical diseases [NTDs] than is suggested by those so vigorously promoting expansion of the approach. This paper fills an important gap: it draws upon local level research to examine the roll out of treatment for two NTDs, schistosomiasis and soil-transmitted helminths, in Uganda. Methods: Ethnographic research was undertaken over a period of four years between 2005-2009 in north-west and south-east Uganda. In addition to participant observation, survey data recording self-reported take-up of drugs for schistosomiasis, soil-transmitted helminths and, where relevant, lymphatic filariasis and onchocerciasis was collected from a random sample of at least 10% of households at study locations. Data recording the take-up of drugs in Ministry of Health registers for NTDs were analysed in the light of these ethnographic and social survey data. Results: The comparative analysis of the take-up of drugs among adults revealed that although most long term residents have been offered treatment at least once since 2004, the actual take up of drugs for schistosomiasis and soil-transmitted helminths varies considerably from one district to another and often also within districts. The specific reasons why MDA succeeds in some locations and falters in others relates to local dynamics. Issues such as population movement across borders, changing food supply, relations between drug distributors and targeted groups, rumours and conspiracy theories about the 'real' purpose of treatment, subjective experiences of side effects from treatment, alternative understandings of affliction, responses to social control measures and historical experiences of public health control measures, can all make a huge difference. The paper highlights the need to adapt MDA to local circumstances. It also points to specific generalisable issues, notably with respect to health education, drug distribution and more effective use of existing public health legislation. Conclusion: While it has been an achievement to have offered free drugs to so many adults, current standard practices of monitoring, evaluation and delivery of MDA for NTDs are inconsistent and inadequate. Efforts to integrate programmes have exacerbated the difficulties. Improved assessment of what is really happening on the ground will be an essential step in achieving long-term overall reduction of the NTD burden for impoverished communities.This article is available through the Brunel Open Access Publishing Fund

Solar Resource Assessment

This report covers the solar resource assessment aspects of the Renewable Systems Interconnection study. The status of solar resource assessment in the United States is described, and summaries of the availability of modeled data sets are provided

On the Second Law of thermodynamics and the piston problem

The piston problem is investigated in the case where the length of the cylinder is infinite (on both sides) and the ratio $m/M$ is a very small parameter, where $m$ is the mass of one particle of the gaz and $M$ is the mass of the piston. Introducing initial conditions such that the stochastic motion of the piston remains in the average at the origin (no drift), it is shown that the time evolution of the fluids, analytically derived from Liouville equation, agrees with the Second Law of thermodynamics. We thus have a non equilibrium microscopical model whose evolution can be explicitly shown to obey the two laws of thermodynamics.Comment: 29 pages, 9 figures submitted to Journal of Statistical Physics (2003

Current Issues in Terrestrial Solar Radiation Instrumentation for Energy, Climate and Space Applications Preprint prepared for New RAD '99

Reductions of uncertainty in terrestrial solar radiation measurements are needed to validate the Earth's radiation balance derived from satellite data. Characterization of solar energy resources for renewable technologies requires greater time and spatial resolution for economical technology deployment. Solar radiation measurement research at the National Renewable Energy Laboratory addresses calibrations, operational characteristics, and corrections for terrestrial solar radiation measurements. We describe progress in measurements of broadband diffuse-sky radiation, and characterization of field instrument thermal offsets and spectral irradiance. The need and prospects for absolute references for diffuse and long-wave terrestrial solar radiation measurements are discussed. Reductions in uncertainty of broadband irradiance measurements from tens of watts per square meter to a few (one to two) watts per square meter are reported, which reduce time and labor to quantify and identify trends in artificial optical radiation sources, terrestrial solar radiation, and the Earth's radiation budget